Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6 * A * (100 - R) = 1.37*10^-6 * 0.4158 * 100 = 0.000057 μg/L = 0.0570 ng/L

Where:

A = 0.4158 kg ceritinib (total sold amount API in Sweden year 2022, data from IQVIA).

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0, if no data is available.

P = number of inhabitants in Sweden = 10 * 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green algae - freshwater (Pseudokirchneriella subcapitata) (Harlan Study Number: D78373)

ErC50 72 h (growth rate) = > 0.49 mg/L

ErC10 72 h (growth rate) = 0.12 mg/L

Crustacean (Daphnia magna, waterflea) (Harlan Study Number: D78362)

Chronic toxicity

NOEC (21 days) = 0.41 mg/L

Fish (Danio rerio, zebrafish)

Chronic toxicity

NOEC (35 days) = 0.045 mg/L (OECD 203) (Harlan Study Number: D78351)

Other ecotoxicity data:

Bacterial Respiration Inhibition

NOEC (3 Hr) = > 100.0 mg/L (activated sludge respiration inhibition, OECD209) Harlan Laboratories Ltd_D78395

PNEC Derivation:

PNEC = 4.5 µg/L (justification of chosen assessment factor (AF))

PNEC (µg/L) = lowest NOEC/10, where 10 is the assessment factor used if chronic toxicity studies from three trophic levels are available. NOEC for chronic fish toxicity study has been used for this calculation since it is the most sensitive endpoint of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000057 µg/L / 4.5 µg/L = 0.000013, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ceritinib has been considered to result in insignificant environmental risk."

Degradation

Ready degradability (28 days) Assessment of Ready Biodegradability in CO2 Evolution Test of LDK378-NXA Harlan Study Nr. D78384

Not readily degradable

Justification of chosen degradation phrase:

Ceritinib did not pass the criteria for ready biodegradability. Therefore, the phrase "the substance is potentially persistent" is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log D = 5.1 (WIL Research Europe B.V., Project 503057)

Justification of chosen bioaccumulation phrase:

Since log D at an environmentally relevant pH is > 4, ceritinib has high a potential for bioaccumulation.

Excretion (metabolism)

Following a single 750 mg ceritinib dose, the geometric mean apparent plasma terminal half-life (t1/2) of ceritinib was 41 hours in patients. Ceritinib demonstrates nonlinear PK over time. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h). In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma. Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.

PBT/vPvB assessment

Ceritinib is potentially persistent based on the ready biodegradation study. It has high a potential for bioaccumulation based on its Log Pow > 4. However, it does not fulfill the criteria for toxicity and thus it cannot be classified as a PBT substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• Harlan Study Number: D78373. Toxicity to Pseudokirchneriella subcapitata in a 72-Hour Algal Growth Inhibition Test.

• Harlan Study Number: D78362. Effect on Survival and Reproduction of Daphnia magna in a Semi-Static Test over Three Weeks.

• Harlan Study Number: D78351. Toxic Effects to Zebra Fish (Danio rerio) in an Early-Life Stage Toxicity Test.

• Harlan Laboratories Ltd_D78395. Toxicity to activated sludge in a Respiration inhibition test.

• Harlan Study Nr. D78384 Assessment of Ready Biodegradability in the CO2 Evolution Test.

• WIL Research Europe B.V., Project 503057 Determination of Physico-Chemical properties